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					                                               Annals of Hepatology 2008; 7(2): April-June: 148-151



                                                               Original Article

     Annals
        of
    Hepatology      Impact of diabetes mellitus on outcome of HCC
                                    Deepak N. Amarapurkar;1 Nikhil D. Patel;2 Praful M. Kamani2


Abstract                                                                    Key words: Hepatocellular carcinoma, Diabetes Mellitus,
                                                                            Non-alcoholic fatty liver disease, Chronic liver disease.
Background: Diabetes mellitus (DM) is recently identi-
fied risk factor for development and progression of                         Introduction
chronic liver disease as well as hepatocellular carcino-
ma (HCC). We planned a prospective analysis to identi-                          Type-2 diabetes mellitus (DM) increases risk of develop-
fy impact of DM in Indian patients with HCC. Methods:                       ment of chronic liver disease (CLD).1 Commonest CLD in
During last 10 years, 160 consecutive patients of HCC                       DM is non-alcoholic fatty liver disease (NAFLD).2 Hepato-
were evaluated. Demographic profile like age of presen-                     cellular carcinoma (HCC) occurs in patients with CLD and
tation, clinical features, etiology of HCC, tumor size at                   mostly in presence of cirrhosis. Known predisposing causes
presentation, management and ultimate outcome was                           of HCC are hepatitis B virus, hepatitis C virus (HCV),
compared diabetic with non-diabetic HCC patients. Re-                       chronic alcohol abuse, hemochromatosis and, recently, non-
sults: During last 10 years, 160 consecutive patients of                    alcoholic fatty liver disease (NAFLD).3 Cryptogenic cirrho-
HCC were evaluated (Mean age = 59.6 ± 12.9 years, sex                       sis remains responsible for HCC in 15-50% cases.4,5
ratio (M: F) = 5.4: 1). Etiology for HCC were hepatitis B                       Although earlier studies denied the association be-
in 45 (28.2%), hepatitis C in 18 (11.3%), alcohol in 27                     tween type-2 diabetes mellitus (DM) and HCC;6-8 in most
(16.8%), alcohol with hepatitis B in 12 (7.5%), alcohol                     of the recent studies, DM is shown to increase risk of HCC
with hepatitis C in 1 (0.6%), non-alcoholic steatohepati-                   by 2- to 4-fold, even after adjusting for other predisposing
tis in 4 (2.5%) and cryptogenic in 53 (33.2%) patients.                     factors.5,9-29 In presence of viral hepatitis and alcohol in-
Patients of HCC with DM (group-A, n =46, age = 62.6 ±                       take, DM increases risk for HCC by 10-fold.25 DM is a ma-
9.5 years, sex (M: F) = 6.6:1) were compared with pa-                       jor risk factor for NAFLD,30-33 which is shown to predis-
tient of HCC without DM (group-B, n =114, age = 66.7 ±                      pose for cryptogenic cirrhosis34 and HCC.35-37 There is in-
13.7 years, sex (M: F) = 5.4:1). Duration of diabetes in                    creased incidence of DM in HCV infection, a known risk
group-A was 7.6 ± 3.2 years. Patients in group-A had                        factor for HCC. Cirrhosis itself is diabetogenic state and
more advanced HCC (size of lesion > 5 cm and >3 le-                         also a predisposition for HCC. Diabetes is a risk factor, if
sions of 3 cm or more diameter, portal vein thrombosis                      not actually etiologic for HCC, but temporal relationship
or intra-hepatic bile duct involvement) than group-B [34                    is not yet clearly defined.9,27 Only few studies have shown
(73.9%) vs 72 (54.3%)]. Mortality with in one year was                      DM to precede HCC.1,38 World-wide, incidence of DM as
significantly more in group-A compared to group-B [36                       well as HCC is increasing.1 India is experiencing an epi-
(78.2%) vs 56 (49.1%)]. Conclusion: DM is associated                        demic of DM.39 Establishing epidemiological relation and
with more advanced lesion and poor outcome in patient                       cause-effect relationship between these two is important.
with HCC.                                                                       There are only few studies on impact of DM on man-
                                                                            agement and outcome of HCC. None of the studies from
1
    Head.                                                                   India have shown relation of DM with HCC. This study
2
    Clinical assistants, Gastroenterology Department, Bombay                was planned to evaluate impact of DM on management
    Hospital and Medical Research Centre, Mumbai.                           and outcome of HCC.
Address for correspondence:
Dr. Deepak Amarapurkar                                                      Materials and methods
D 401/402 Ameya RBI Employees
Co-Op Housing Society,                                                         This case-control observational study was carried out
Plot No. 947-950
New Prabhadevi Road
                                                                            over study period of 10 years (1997-2006) on all the con-
Prabhadevi                                                                  secutive patients of HCC. Diagnosis of HCC was based on
Mumbai 400 025                                                              hyper-vascular tumor in the liver on two imaging studies
Telephone No. 91 22 24306262/24222432                                       or hyper-vascular tumor on single imaging modality with
Fax No. 91 22 24368623
E-mail: amarapurkar@gmail.com; amarapurkar@vsnl.com
                                                                            serum alpha-fetoprotein level greater than 400 ng/dL.
                                                                               Patients were divided into 2 groups: a) Diabetic pa-
Manuscript received and accepted: 25 April 2008                             tients with HCC and b) Non-diabetic patients with HCC.
                                           DN Amarapurkar et al. Impact of diabetes mellitus on outcome of HCC                               149

Diabetes was diagnosed according to American Diabetes                           Discussion
Association criteria on the basis of use of oral hypogly-
cemic drugs; fasting plasma glucose level ≥ 126 mg/dL;                              Previously, DM is shown to be a bad prognostic factor
2-hour plasma glucose ≥ 200 mg/dL during oral glucose                           for long-term survival of cirrhotic patients and mortality
tolerance test; and/or random or 2-hour post-prandial                           mainly being related to liver failure.40
plasma glucose level ≥ 200 mg/dL.                                                   Among 7 studies done to find out impact of DM on
   In both groups following features were noted: age of                         HCC management, with few exceptions, most have
presentation, clinical features, laboratory features, Child                     shown increased post-resection complications and de-
class (CPT score), etiology (hepatitis B, hepatitis C, alco-                    creased post-resection survival, most probably due to in-
hol, NASH or other etiologies), tumor characteristics at                        creased risk of hepatic decompensation in DM.41-47 In our
presentation (advanced HCC), management (resection                              study, DM is associated with morphologically advanced
and ablative therapy or palliative management) and sur-                         lesions and with advanced liver disease regardless of eti-
vival. Advanced HCC (morphological) was diagnosed on                            ology. This can be a deciding factor for delineating man-
basis of tumor size > 5 cm or > 3 tumors each measuring >                       agement strategies, namely surgical resection, percutane-
3 cm diameter or portal vein thrombosis or bile duct in-                        ous therapies and trans-arterial chemoembolization. Our
vasion.                                                                         study also shows that DM has adverse prognosis in HCC
   Statistical analysis was performed using Chi square                          with high 1-year mortality rate.
test and student t test.                                                            It is still unclear whether HCC occurs because of insu-
                                                                                lin resistance, which leads to NASH, which leads to cir-
Results                                                                         rhosis, or whether the stimulatory effects of insulin on
                                                                                hepatocyte growth lead more directly to neoplasia. Re-
    As seen in Table I, majority of the patients in both                        cent studies have thrown light on how DM leads to HCC.
groups were in age group 51-70 years. There was no sta-                         DM is a state of hyperinsulinemia. Hyperinsulinemia
tistically significant difference in both the study groups                      may directly induce HCC: 1. by the up-regulation of re-
regarding age distribution.                                                     ceptors of specific growth factors (insulin and insulin-
    Different etiologies of HCC are tabulated in Table II.                      like-growth factor-1);48,49 2. by activating mitogen acti-
As an etiology for HCC, alcohol and NASH were signifi-                          vated kinase that leads to phosphorylation of insulin re-
cantly higher in group-A.                                                       ceptor substance-1(IRS-1) a key protein involve in
    As seen in Table III, in group-A there was higher child                     cellular proliferation.50,51 Insulin resistance may play a
class C patients and more advanced HCC. Also there was                          role by increasing oxidative stress and generation of reac-
lower rate of curative treatment for HCC. Mortality rates                       tive oxygen species that leads to a. p53 tumor suppressor
at 1-year were higher in group-A.                                               gene mutation via by-product of lipid peroxidation (4-
                                                                                hydroxynoneal),52,53 or b. up-regulation of proinflamma-
                                                                                tory cytokines. Thus, inflammation, cellular prolifera-
                                                                                tion, apoptosis inhibition and tumor suppressor gene mu-
Table I. Age-wise distribution.                                                 tations in setting of advanced liver disease (as a result of
                                                                                insulin resistance and hyperinsulinemia) may lead to
Age in years,        Group A,               Group B,
n (%)                 n = 46                n = 114              p

< 50                  8 (17.4)             17   (14.9)          NS              Table III. Presenting features and outcome of both groups.
51-60                13 (28.3)             28   (24.6)          NS
61-70                19 (41.3)             46   (40.3)          NS                                               Group A,      Group B,
> 70                   6 (13)              23   (20.2)          NS              Parameters                        n = 46        n=114        p

                                                                                Mean age, year               62.6 ± 9.5       66.7 ± 13.7    NS
                                                                                Sex ratio (M:F)                 6.6:1            5.4:1       NS
                                                                                Mean duration of
Table II. Different etiologies of HCC.                                          Diabetes, years               7.6 ± 3.2            ---        -
                                                                                Mean CPT score               11.8 ± 2.6        10.2 ± 2.1    NS
Etiology, n (%)          Group A,        Group B,               Total           Child class C, n (%)         37 (80.4)         70 (61.4)     S
                          n = 46         n = 114         p     n = 160          α-fetoprotein
                                                                                (> 400 ng/dL), n (%)         16 (34.8)         46 (40.3)     NS
Hepatitis B alone        11 (23.9)       34 (29.8)       NS   45 (28.1)         Mean α-fetoprotein,
Hepatitis B with alcohol 6 (13)           6 (5.3)        NS    12 (7.5)         ng/dL                      1864.5 ± 441.5    2309 ± 726.6    NS
Alcohol alone            14 (30.4)       13 (11.4)        S   27 (16.8)         Advanced lesions, n (%)      34 (73.9)         62 (54.3)      S
Hepatitis C alone          2 (4.3)        16 (14)        NS   18 (11.3)         Resection or ablative
Hepatitis C with alcohol    0 (0)         1 (0.9)        NS    1 (0.6)          therapy, n (%)                 4 (8.6)         20 (17.5)     S
NASH                       4 (8.7)         0 (0)          S    4 (2.5)          Mean survival, months        10.1 ± 3.1        18.7 ± 6.1    S
Cryptogenic               9 (19.6)       44 (38.6)        S   53 (33.1)         Mortality at 1-year, n (%)   36 (78.2)         56 (49.1)     S
150                                                       Annals of Hepatology 7(2) 2008: 148-151

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